Rh2(OAc)4-catalyzed reaction of α-diazocarbonyl compounds with 2-carbonyl-substituted 2H-azirines

Article abstract of DOI:10.1016/j.tet.2013.04.022

The Rh₂(OAc)₄-catalyzed reaction of 2H-azirine-2-carbaldehydes with dimethyl diazomalonate proceeds via azirinium ylide formation, isomerization to 2-azabuta-1,3-dienes followed by 1,6-π-electrocyclization to give 2H-1,3-oxazines. Ac

Full text of DOI:10.1016/j.tet.2013.04.022

Tetrahedron 69 (2013) 4546e4551
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journal homepage: www.elsevier.com/locate/tet
Rh2(OAc)4-catalyzed reaction of a-diazocarbonyl compounds with
2-carbonyl-substituted 2H-azirines
,
a
b
Kirill V. Zavyalov a, Mikail S. Novikova , Alexander F. Khlebnikov , Dmitry S. Yufit
*
a Department of Chemistry, Saint-Petersburg State University, Universitetskii pr. 26, 198504 St. Petersburg, Russia
b Department of Chemistry, Durham University, South Rd., Durham DH1 3LE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The Rh2(OAc)4-catalyzed reaction of 2H-azirine-2-carbaldehydes with dimethyl diazomalonate proceeds
via azirinium ylide formation, isomerization to 2-azabuta-1,3-dienes followed by 1,6- -electrocyclization
Received 13 February 2013
Received in revised form 19 March 2013
Accepted 4 April 2013
p
to give 2H-1,3-oxazines. According to DFT-calculations ring opening of azirinium ylides should occur
stereoselectively to give 2-azadienes with the C]C bond exclusively in the Z configuration. Changing
a formyl group for an acetyl group in the azirine leads to a lowering of stereoselectivity and the formation
of azadienes with an E configuration of the C]C bond was observed. The reaction of 2-acyl-2-
diazoacetates with 2H-azirine-2-carbaldehydes proceeds similarly, but the 2-acetyl-substituted 2H-1,3-
oxazines formed are unstable under chromatographic purification and rearrange easily into pyrrole
derivatives.
Available online 10 April 2013
Keywords:
Azirines
Diazo compounds
Carbenoids
Ylides
Ó 2013 Elsevier Ltd. All rights reserved.
Electrocyclic reactions
1. Introduction
however, only a few examples inwhich 2H-azirine ring enlargement
occurs under metallocarbenoid action. An azetine derivative was
Metal-catalyzed decomposition of diazo compounds proceeding
through reactive carbenoids is an effective method for the synthesis
of various heterocyclic systems. Considerable progress has been
achieved in the development of methods using intramolecular re-
actions of metallocarbenoids, leading to cycle formation with high
yields and stereoselectivity. Intermolecular reactions of carbenoids
with heteroatomic molecules, which allow the use of more simple
and available starting materials are also well known and exten-
sively developed. The reactions of metallocarbenoids with mono-
heterocyclic substrates can result in the formation of ortho-fused1
or bridged2 heterocyclic systems, the products of formal CeH
insertion1d,2a,3 and recyclization, which can occur with retention of
ring size,4 ring contraction5 or with ring enlargement. Carbenoid-
mediated ring enlargement can occur as one-carbon ring expan-
sion by formal insertion of a carbene moiety into the carbon-
eheteroatom bond6 or a three-atom ring expansion. The latter
reaction type implies the involvement of the atoms of a carbonyl
function or an alkenyl moiety, which can be located either in the
starting heterocycle6e,7 or in the diazo compound.8
synthesized in good yield from 2,3-diphenyl-2H-azirine and di-
methyl diazomalonate under Rh(II)-catalysis.10 Three-atom ring
expansion of the azirine ring to the 2H-1,4-oxazine system was
observed in the reaction of aryl-substituted 2H-azirines with ethyl
2-acyl-2-diazoacetates carried out in the presence of Rh2(OAc)4.11
The carbene carbon atom and two carbonyl atoms of acyl function
of the diazo compound take part in a new cycle formation. To the
best of our knowledge the carbenoid-mediated ring-enlargements
of 2H-azirines with substituents on the azirine ring are unknown.
In order to broaden the scope of the applications of reactions of
2H-azirines with metallocarbenoids in heterocyclic synthesis the
examination of the Rh2(OAc)4-catalyzed reaction of 2-carbonyl-
subsituted 2H-azirines with dimethyl diazomalonate and ethyl 2-
acyl-2-diazoacetates is the subject of the present work.
2. Results and discussion
Earlier it was found that the result of the Rh2(OAc)4-catalyzed
reaction of dimethyl diazomalonate with aryl-substituted 2H-azir-
ines A dramatically depends on a number of aryl substituents in the
three-membered ring. The reaction of 2-phenyl-2H-azirine gives
two products: 2-azadiene B and the product of formal double in-
sertion of di(methoxycarbonyl)carbene into three-membered ring,
pyrroline C (Scheme 1). The reaction of 2,3-diphenylazirine pro-
duces the product of formal insertion of di(methoxycarbonyl)
2H-Azirine derivatives are effective heterocyclic building blocks
used for the construction of larger ring heterocycles.9 There are,
* Corresponding author. Tel.: þ7 812 428 4021; fax: þ7 812 428 6939; e-mail
address: m.s.novikov@chem.spbu.ru (M.S. Novikov).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.022

K.V. Zavyalov et al. / Tetrahedron 69 (2013) 4546e4551
4547
Table 1
The yields of 2H-1,3-oxazines 5aef
Azirine
R1
1a Ph
R2
Oxazine
Yield of 5, %
H
H
H
H
Me
Ph
5a
5b
5c
5d
5e
5f
26
23
42
35
17
44
1b
1c
1d
1e
1f
4-MeOC6H4
4-ClC6H4
4-MeC6H4
Ph
Ph
The azadiene E-4g along with oxazine 5g were isolated by
chromatography after reacting the 2-acetyl-substituted azirine 1g
with dimethyl diazomalonate (Scheme 3). The E configuration of
the compound E-4g was elucidated by X-ray analysis (Fig. 1). This
compound undergoes fast N-inversion in CDCl3 solution, since only
one singlet of the two ester methyl groups was observed in the 1H
NMR spectrum, as well as only one signal for two carbonyl atoms
appeared in the 13C NMR spectrum. Notably, the absence of an
electron-withdrawing substituent at the 4-position of the 2-
azabuta-2,4-diene fragment is responsible for the increase of the
inversion barrier so that at ambient temperature the corresponding
atoms of azadienes B and E (Scheme 1) are not equivalent.10b
No traces of the stereoisomer Z-4g were detected in the reaction
mixtures and this can be explained by its fast cyclization into
oxazine 5g under reaction conditions. 1H NMR monitoring of the
reaction mixtures showed that the 5g:E-4g ratio was 6:1 and did
not change during the reaction course.
Scheme 1. Rh2(OAc)4-catalyzed reaction of aryl-substituted 2H-azirines with dimethyl
diazomalonate.
carbene into three-membered ring, azetine D, while from tri-
substituted azirine, 3-phenyl-2H,90H-spiro[azirine-1,90-fluorene]
only 2-azadiene E was obtained as a sole product. The formation of
these compounds was explained by transformations of azirinium
ylides, which are primary intermediates in the reactions of carbe-
noids with azirines.
The introduction of a formyl group in the C2 position of the
azirine ring completely changes the result of its interaction with
Rh(II)-carbenoid derived from dimethyl diazomalonate (2a). The
slow addition of diazo compound 2a in 1,2-dichloroethane (DCE) to
a solution of methyl 3-phenyl-2H-azirine-2-carbaldehyde (1a), in
the presence of 5 mol % of Rh2(OAc)4 in DCE under reflux, gave 2H-
1,3-oxazine 5a, which was isolated in 26% yield using column
chromatography on silica gel (Scheme 2). According to 1H NMR
spectroscopy data, no traces of products of the types BeE (Scheme
1) containing a formyl group were ever present in the reaction. The
reaction mechanism can be rationalized in terms of the formation
of azirinium ylide 3, its ring-opening into 2-azadiene 4 followed by
1,6-electrocyclization with the participation of the formyl carbonyl
group (Scheme 2).
The reaction of azirinecarbaldehydes
1 with ethyl diazo-
acetoacetate 2b, under Rh(II)-catalysis would produce a 2-azadiene
with two carbonyl functions at the C1 and C4 atoms (acetyl and
formyl groups), which both could be involved in 1,6-cyclization to
give 2H-1,4- or 2H-1,3-oxazine, respectively. In order to examine
the competition of these two electrocyclizations we carried out the
reaction of azirine 1b with diazo keto ester 2b in DCE in the pres-
ence of Rh2(OAc)4. Surprisingly, neither 1,3-oxazine 8 nor 1,4-
oxazine 9 but only pyrrolinone 10 was isolated after chromato-
graphic purification of the reaction mixture (Scheme 4).
According to the 1H NMR, the main component of the reaction
mixture was 1,3-oxazine 8: 2.37 (s, 3H), 3.87 (s, 3H), 6.08 (d,
J¼5.9 Hz, 1H), 6.96 (d, J¼8.7 Hz, 2H), 7.87 (d, J¼8.7 Hz, 2H). All at-
tempts to separate this compound by crystallization at the lowered
temperature failed. When the mixture was subjected to chroma-
tography on silica gel the oxazine 8 was completely converted into
pyrrolinone 10. The structure of the compound 10 was verified by
1H, 13C NMR, IR spectroscopy, mass spectrometry, and elemental
analysis. Presumably, under acidic conditions a recyclization of 1,3-
oxazine via 2-azadiene 7 to 2-hydroxypyrroline 11 followed by
a 1,5-sigmatropic shift is occurring.
Only pyrrole 12 was isolated in low yield in the reaction of
azirine 1b with ethyl benzoyldiazoacetate 2c (Scheme 5). After the
chromatographic work-up of the reaction mixture no products
formed by 1,6-cyclizations of the intermediate 2-azadiene were
observed. The structure of pyrrole 12 was determined by standard
spectroscopic methods and confirmed by X-ray analysis (Fig. 1). The
formation of this compound can be explained by considering the
same mechanism as above giving a 2-hydroxypyrrole derivative,
which then disproportionates.
The final products of the catalytic reaction of diazoacetoacetate
2c with 2H-azirine-2-carbaldehydes 1 are thereby shown to be the
2-acyl-substituted 2H-1,3-oxazines 8, but these then undergo
a rapid rearrangement under chromatographic purification condi-
tions. That the oxazines 8 are the preferable structures in the re-
action was confirmed by quantum-chemical calculations of ring-
opening of isomeric E- and Z-ylides 13 to isomeric 2-azazadienes
E-14 and Z-14, followed by their interconversions via N-inversion
and 1,6-cyclizations to 1,3- and 1,4-oxazines 15 and 16 (Scheme 6).
Scheme 2. Rh2(OAc)4-catalyzed reaction of 2-carbonyl-substituted 2H-azirines 1aef
with dimethyl diazomalonate 2a.
Using this procedure 4-aryl-2H-1,3-oxazines 5bed were ob-
tained in 23e42% yield (Table 1). The introduction of an additional
methyl or phenyl group into position 2 of the azirine ring does not
change the course of the reaction, which is controlled by the 2-
formyl group to give exclusively 1,3-oxazines 5e, f. In the 1H NMR
spectra of the reaction mixtures only traces of products containing
a formyl group were observed.
All the newly obtained compounds were fully characterized
using standard spectral and analytical methods. The structure of 5a
was confirmed by X-ray analysis (Fig. 1).

4548
K.V. Zavyalov et al. / Tetrahedron 69 (2013) 4546e4551
Fig. 1. X-ray structure of compounds E-4g, 5a, and 12.
Scheme 3. Rh2(OAc)4-catalyzed reaction of azirine 1g with dimethyl diazomalonate 2a.
Scheme 6. The transformation of azirinium ylides E-13 and Z-13 into oxazines 15, 16.
Scheme 4. Rh2(OAc)4-catalyzed reaction of azirine 1b with ethyl diazoacetoacetate 2b.
The geometries of ylides E-13, Z-13, azadienes E,E-, E,Z-, Z,E-, and
Z,Z-14,1,3-oxazine 15,1,4-oxazine 16, as well as the transition states
of ring opening of ylides 13 (TS1eTS4), 1,6-cyclizations of azadienes
14 in oxazines 15, 16 (TS5eTS8), E,Z-isomerization of ylides 6aec
(TS9) and isomerization of azadienes 14 (TS10) were optimized at
the DFT mPWB1K/6-31þG(d,p) level12 using the PCM solvent
model for 1,2-dichloroethane (Scheme 6).
The energy of the most stable conformation of each isomeric
azadiene was used for calculations of the activation free energies
(Fig. 2).
Computations show that the ring-opening of the isomeric ylides
E- and Z-13 to azadienes 14 must occur with high stereoselectivity
to give the E,Z- and Z,Z-isomers, both having exclusively a Z con-
figuration of the C]C bond: the energies of TS1 and TS2 are higher
than those of TS3 and TS4 by 3e4 kcal/mol. Activation energies of
azadienes E,Z- and Z,Z-14 formation are about 9e11 kcal/mol and
are comparable to the barrier values for their 1,6-cyclization to 1,3-
oxazine 15 (11e12 kcal/mol). Considering that fact that the free
energy for 1,3-oxazine 15 is lower than the energy of any azadiene
isomer 14, one can conclude that the 1,6-cyclization of 14 to 15 is
a kinetically and thermodynamically favorable process. 1,4-Oxazine
16 can be formed either from E,Z-14 or E,E-14, the last of, which
Scheme 5. Rh2(OAc)4-catalyzed reaction of azirine 1b with ethyl 2-benzoyl-2-
diazoacetate 2c.

K.V. Zavyalov et al. / Tetrahedron 69 (2013) 4546e4551
4549
stereoselectivity, and the formation of azadienes with an E con-
figuration of the C]C bond can be observed. The analogous re-
action of 2-acyl-2-diazoacetates proceeds in a similar manner, but
the final 2-acetyl-substituted 2H-1,3-oxazines are unstable under
chromatographic purification conditions and rearrange into pyrrole
derivatives.
4. Experimental section
4.1. General methods
Melting points were determined on a hot stage microscope and
are uncorrected. 1H (300 MHz) and 13C (75 or 150 MHz) NMR
spectra were determined in CDCl3 and DMSO-d6. Chemical shifts (d)
are reported in parts per million downfield from tetramethylsilane.
Electrospray ionization mass spectra were measured on a Bruker
micrOTOF mass spectrometer. Elemental analysis was performed
on a HewlettePackard 185B CHN-analyser. IR spectra were recor-
ded on a SPECORD M80 spectrometer for solutions in CHCl3. Single
crystal X-ray data were collected on a Bruker SMART-6000 (com-
pounds 5a and E-4g) and on an Agilent Gemini S-Ultra (compound
12) diffractometers equipped with Cryostream (Oxford Cry-
Fig. 2. Energy profiles (mPWB1K/6-31þG(d,p), kcal/mol, 357.15 K) for the trans-
formations of ylides E-13, Z-13 to oxazines 15, 16 in 1,2-dichloroethane.
cyclizes much more rapidly. But as was mentioned above the E,E-14
isomer does not form in the reaction, and the 1,4-oxazine 16 can
therefore arise only from azadiene E,Z-14 via transition state TS6
with an extremely high activation barrier (31.3 kcal/mol). This route
of stabilization of the azadiene E,Z-14 cannot compete with its
osystems) open-flow nitrogen cryostates at 120 K using graphite
ꢀ
monochromated (MoK
a
)-radiation (
l
¼0.71073 A). All structures
1,6-cyclization to 1,3-oxazine 15 proceeding with
D
Gs¼12 kcal/
were solved by direct methods and refined by full-matrix least
squares on F2 for all data using SHELXTL13 and OLEX214 software. All
non-hydrogen atoms were refined with anisotropic displacement
parameters, H-atoms were located on the difference map and re-
fined isotropically. Crystallographic data for the structures have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC-920501 (for E-4g), CCDC-
920502 (for 5a), and CCDC-920503 (for 12). Silica gel Merck 60
was used for column chromatography. Thin-layer chromatography
(TLC) was conducted on alumina sheets precoated with SiO2 ALU-
GRAM SIL G/UV254. Compounds 1aeg,15 and 2a,16 b,c17 were pre-
pared by the reported procedures.
mol. On the other hand, the more preferable 1,4-oxazine 16
precursor, E,E-14, can be formed from Z,E-14 via N-inversion of the
C]N bond (TS10, Fig. 2), the activation barrier of, which is 14.1 kcal/
mol. A sufficiently low activation barrier, however, was evaluated
for ring-opening of ylide Z-13 to Z,Z-isomer but not to Z,E-14.
From the analysis of transition states TS5, TS6 structures one can
suppose that one of the reasons for such a dramatic influence of the
configuration of the C]C bond of azadiene on the barrier of its
cyclization to the 1,4-oxazine is in disturbance of the conjugation in
the transition state of the azadiene system with the formyl group,
located cis to nitrogen. According to the calculations dihedral angle
C3eC4eC]O in transition state TS6 is 75.2ꢀ, while in TS5 this value
is only 17.7ꢀ.
4.2. Calculation details
Hence, the main reason for the absence of 2H-1,4-oxazine de-
rivatives among the products of the reaction is Z-stereoselectivity
of ring opening of the ylide intermediate.
In azadiene 1h, with a protected formyl group, derived from
azirine 1h and diazo compound 2c, the cyclization to 1,3-oxazine
is blocked, and 1,4-oxazine 17 was isolated as a sole product
(Scheme 7).
All calculations were performed with the mPWB1K density
functional method by using the Gaussian 09 suite of quantum
chemical programs.18 Geometry optimizations of intermediates,
transition states, reactants, and products in 1,2-dichloroethane
were performed at the DFT mPWB1K/6-31þG(d,p) level using
PCM model. Stationary points on the respective potential-energy
surfaces were characterized at the same level of theory by evalu-
ating the corresponding Hessian indices. Careful verification of the
unique imaginary frequencies for transition states was carried out
to check whether the frequency indeed pertains to the desired
reaction coordinate. Intrinsic reaction coordinates (IRC) were cal-
culated to authenticate the transition states.
Scheme 7. Rh2(OAc)4-catalyzed reaction of azirine 1h with ethyl 2-benzoyl-2-
diazoacetate 2c.
4.3. Reactions of azirines 1aef with diazo compounds 2aec
3. Conclusions
4.3.1. General procedure. A 1.0 M solution of diazo compound 2aec
in anhydrous 1,2-dichloroethane (DCE) was added dropwise with
a syringe at a rate of 1.0 mL/h to a stirred 1.0 M solution of azirine
1aef and Rh2(OAc)4 (7 mol % on azirine) in anhydrous DCE at reflux
under an argon atmosphere until the azirine was consumed com-
pletely (control by TLC). The solvent was evaporated in vacuo, and
the residue was purified by column chromatography on silica gel
(eluent hexane/EtOAc) to give, after crystallization from the solvent
indicated below, compound 5aeg.
In conclusion, we have reported the first example of a three-
atom ring expansion of 2H-azirines to 1,3-oxazine system. This
transformation is the result of the Rh2(OAc)4-catalyzed reaction of
2H-azirine-2-carbaldehydes with dimethyl diazomalonate. The
reaction proceeds via azirinium ylides formation, ring opening to
2-azabuta-1,3-dienes followed by a 1,6-p-electrocyclization to the
2H-1,3-oxazines. According to DFT-calculations ring opening of
azirinium ylides occurs stereoselectively to give 2-azadienes with
the C]C bond exclusively in the Z configuration. Changing a formyl
group for an acetyl group in the azirine leads to a lowering of
4.3.2. Dimethyl 4-phenyl-2H-1,3-oxazine-2,2-dicarboxylate (5a).
Compound 5a was prepared according to the general procedure

4550
K.V. Zavyalov et al. / Tetrahedron 69 (2013) 4546e4551
from azirine 1a (103 mg, 0.71 mmol) and diazo compound 2a
(112 mg, 0.71 mmol) as a colorless solid (50 mg, 26%). Mp 90e91ꢀS
(hexane/Et2O); Rf (33% EtOAc/hexane) 0.33; IR (KBr): 3089, 2966,
167.9 (C-4). HRMS (ESI-TOF, [MþH]þ): calcd for C15H16NO5,
290.1023; found 290.1027.
1756, 1632, 1580, 1534 cmꢁ1 1H NMR (300 MHz, CDCl3):
d
3.90 (s,
4.3.7. Dimethyl 4,5-diphenyl-2H-1,3-oxazine-2,2-dicarboxylate (5f).
Compound 5f was prepared according to the general procedure
from azirine 1f (100 mg, 0.45 mmol) and diazo compound 2a
(107 mg, 0.68 mmol) as a light yellow solid (49 mg, 31%). Mp
71e74 ꢀC (hexane/Et2O); Rf (33% EtOAc/hexane) 0.39; IR (KBr):
6H, 2CH3O), 6.15 (d, 1H, J¼5.8 Hz, H-5), 7.14 (d, 1H, J¼5.8 Hz, H-6),
7.42e7.53 (m, 3H, ArH), 7.88e7.90 (m, 2H, ArH). 13C NMR (75 MHz,
CDCl3): d 53.6 (2C, CH3O), 90.7 (C-2), 100.4 (C-5), 127.1, 128.6, 131.5,
135.3 (Ar), 152.5 (C-6), 161.8 (C]O), 166.4 (C-4). HRMS (ESI-TOF,
[MþH]þ): calcd for C14H14NO5, 276.0866; found 276.0854. Anal.
Calcd for C14H13NO5: C, 61.09; H, 4.76; N, 5.09. Found: C, 61.06; H,
4.60; N, 5.34. Crystal data: C14H13NO5, M¼275.25, orthorhombic,
2960, 1765, 1635, 1535 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
3.93
(s, 6H, 2CH3O), 6.98e7.02 (m, 2H, ArH), 7.19e7.39 (m, 9H, H-6, ArH).
13C NMR (75 MHz, CDCl3):
53.7 (2C, CH3O), 90.3 (C-2), 119.1 (C-5),
d
3
ꢀ
ꢀ
a¼6.0659(3), b¼7.6566(4), c¼28.7710(15) A, V¼1336.25(12) A ,
127.5, 127.8, 128.2, 128.5, 129.2, 130.1, 133.7, 136.0 (Ar), 149.9 (C-6),
165.9 (C-4), 166.4 (2C, C]O). HRMS (ESI-TOF, [MþH]þ): calcd for
C20H18NO5, 352.1179; found 352.1185.
T¼120 K, space group P212121, Z¼4,
m(MoK
a
)¼0.105 mmꢁ1, 14,210
reflections measured, 1987 unique (Rint¼0.0691) were used in all
calculations. The final R1 was 0.0447 (1519>2
s
(I)), wR2¼0.1150
(all data).
4.3.8. Dimethyl (E)-2-[(4-oxo-3-phenylpent-2-en-2-yl)imino]malo-
nate (E-4g) and dimethyl 4,6-dimethyl-5-phenyl-2H-1,3-oxazine-2,2-
dicarboxylate (5g). Azadiene E-4g (16 mg, 9%) and oxazine 5g
(77 mg, 44%) were prepared according to the general procedure from
azirine 1g (100 mg, 0.58 mmol) and diazo compound 2a (131 mg,
0.83 mmol). Compound E-4g, orange solid, mp 54e55 ꢀC (hexane/
4.3.3. Dimethyl 4-(4-methoxyphenyl)-2H-1,3-oxazine-2,2-dicarboxy-
late (5b). Compound 5b was prepared according to the general
procedure from azirine 1b (105 mg, 0.6 mmol) and diazo com-
pound 2a (142 mg, 1.2 mmol) as a light yellow solid (69 mg, 23%).
Mp 81e83 ꢀC (hexane/Et2O); Rf (50% EtOAc/hexane) 0.44; IR
Et2O).1H NMR (300 MHz, CDCl3):
3.82 (s, 6H, 2CH3O), 7.07e7.10 (m, 2H, ArH), 7.28e7.35 (m, 3H, ArH).
13C NMR (75 MHz, CDCl3):
18.9 (CH3), 31.1 (CH3), 53.1 (2C, CH3O),
d 2.03 (s, 3H, CH3), 2.34 (s, 3H, CH3),
(KBr): 2963, 1764, 1633, 1600 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d
3.85 (s, 3H, CH3O), 3.89 (s, 6H, CH3O), 6.12 (s, 1H, J¼5.8 Hz, H-5),
d
6.93 (d, 2H, J¼8.7 Hz, ArH), 7.11 (d, 1H, J¼5.8 Hz, H-6), 7.86 (d, 2H,
100.1 (C-3), 121.4 (C-2), 127.6, 128.5, 129.7, 136.2 (Ar), 148.5 (C]N),
153.1 (2C, C]O), 200.0 (C]O). Crystal data: C16H17NO5, M¼303.3,
J¼8.7 Hz, ArH). 13C NMR (75 MHz, CDCl3):
d 53.6 (2C, CH3O), 55.4
ꢀ
(CH3O), 90.7 (C-2), 100.3 (C-5), 113.8, 127.7, 128.9 (Ar), 152.2 (C-6),
160.8 (Ar), 162.4 (C-4), 166.6 (2C, C]O). HRMS (ESI-TOF,
[MþH]þ): calcd for C15H16NO6, 306.0972; found 306.0968. Anal.
Calcd for C15H15NO6: C, 59.01; H, 4.95; N, 4.59. Found: C, 59.02;
H, 4.80; N, 4.76.
triclinic, space group P-1, a¼8.2133(3), b¼8.ꢀ6001(3), c¼12.2957(4) A,
3
ꢀ
a
¼97.967(1),
b
¼100.663(1),
g
¼113.603(1) , V¼759.98(5) A , Z¼2,
T¼120 K,
m
(MoK
a
)¼0.099 mmꢁ1, 12,704 reflections measured, 4048
unique (Rint¼0.0315) were used in all calculations. The final R1 was
0.0398 (3286>2s(I)) and wR2 was 0.1173 (all data).
Compound 5g, colorless solid, mp 103e104 ꢀC (hexane/Et2O); Rf
4.3.4. Dimethyl 4-(4-chlorophenyl)-2H-1,3-oxazine-2,2-dicarboxy-
late (5c). Compound 5c was prepared according to the general
procedure from azirine 1c (108 mg, 0.6 mmol) and diazo compound
2a (95 mg, 0.6 mmol) as a light yellow oil (78 mg, 42%). 1H NMR
(50% EtOAc/hexane) 0.37; IR (KBr): 2958, 2924, 2852, 1749,
1658 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
1.90 (s, 3H, CH3), 1.91
(s, 3H, CH3), 3.90 (s, 6H, CH3O), 7.07e7.10 (m, 2H, ArH), 7.31e7.41
(m, 3H, ArH). 13C NMR (75 MHz, CDCl3):
17.1 (CH3), 23.6 (CH3),
d
(300 MHz, CDCl3):
d
3.90 (s, 6H, 2CH3O), 6.09 (d, 1H, J¼5.8 Hz, H-5),
53.5 (2C, CH3O), 90.2 (C-2), 115.9 (C-5), 127.8, 128.6, 130.2, 134.3
(Ar), 158.2 (C-6), 166.7 (C-4), 166.9 (2C, C]O). HRMS (ESI-TOF,
[MþH]þ): calcd for C16H18NO5, 304.1179; found 304.1199.
7.14 (d, 1H, J¼5.8 Hz, H-6), 7.41 (d, 2H, J¼8.5 Hz, ArH), 7.83 (d, 2H,
J¼8.5 Hz, ArH). 13C NMR (75 MHz, CDCl3):
d 53.7 (2C, CH3O), 90.6
(C-2), 100.0 (C-5), 128.5, 128.8, 133.6, 137.8 (Ar), 152.8 (C-6), 160.8
(C-4), 166.2 (2C, C]O). HRMS (ESI-TOF, [MþH]þ): calcd for
C14H13NO5Cl, 310.0477; found 310.0471.
4.3.9. Ethyl 4-formyl-3-methyl-5-(4-methoxyphenyl)-2-oxo-2,3-
dihydro-1H-pyrrole-3-carboxylate (10). Compound 10 (143 mg,
55%) was prepared according to the general procedure from azirine
1d (150 mg, 0.86 mmol) and diazo compound 2b (334 mg,
2.14 mmol) as a light yellow solid; mp 135e137 ꢀC (Et2O); Rf (33%
EtOAc/hexane) 0.35; IR (KBr): 3176, 2981, 2940, 1750, 1713, 1644,
4.3.5. Dimethyl 4-(4-methylphenyl)-2H-1,3-oxazine-2,2-dicarboxy-
late (5d). Compound 5d was prepared according to the general
procedure from azirine 1d (70 mg, 0.44 mmol) and diazo com-
pound 2a (70 mg, 0.44 mmol) as a light yellow solid (45 mg, 35%).
Mp 129e131 ꢀC (Et2O/hexane); Rf (33% EtOAc/hexane) 0.36; IR
(KBr): 3086, 2966, 1769, 1754, 1629, 1530 cmꢁ1. 1H NMR (300 MHz,
1602 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
1.21 (t, 3H, J¼7.3 Hz, CH3),
1.72 (s, 3H, CH3), 3.91 (s, 3H, CH3O), 4.12e4.27 (m, 2H, CH2), 7.06
(d, 2H, J¼8.7 Hz, ArH), 7.60 (d, 2H, J¼8.7 Hz, ArH), 9.26 (s, 1H, NH),
CDCl3):
d
2.40 (s, 3H, CH3), 3.89 (s, 6H, 2CH3O), 6.13 (d, 1H, J¼5.8 Hz,
9.64 (s, 1H, HC]O). 13C NMR (75 MHz, CDCl3):
d 13.9 (CH3), 18.8
H-5), 7.12 (d, 1H, J¼5.8 Hz, H-6), 7.24 (d, 2H, J¼8.0 Hz, ArH), 7.79 (d,
(CH3), 55.6 (CH3O), 56.7 (C-3), 62.0 (CH2), 114.8, 119.3, 121.2, 130.4,
157.1, 162.7, 167.6, 178.0, 184.0 (Ar, NC]O, OC]O, HC]O). HRMS
(ESI-TOF, [MþK]þ): calcd for C16H17NO5K, 342.0738; found
342.0757. Anal. Calcd for C16H17NO5: C, 63.36; H, 5.65; N, 4.62.
Found: C, 62.96; H, 5.49; N, 4.76.
2H, J¼8.0 Hz, ArH). 13C NMR (75 MHz, CDCl3):
d 21.4 (CH3), 53.6 (2C,
CH3O), 90.7 (C-2), 100.4 (C-5), 127.1, 129.2, 132.5, 142.0 (Ar), 152.3
(C-6), 161.5 (C-4), 166.5 (2C, C]O). HRMS (ESI-TOF, [MþH]þ): calcd
for C15H16NO5, 290.1023; found 290.1029. Anal. Calcd for
C15H15NO5: C, 62.28; H, 5.23; N, 4.84. Found: C, 61.99; H, 5.06; N,
5.08.
4.3.10. 5-(Ethoxycarbonyl)-2-(4-methoxyphenyl)-4-phenyl-1H-pyr-
role-3-carboxylic acid (12). Compound 12 (25 mg, 12%) was pre-
pared according to the general procedure from azirine 1d (100 mg,
0.57 mmol) and diazo compound 2c (311 mg, 1.43 mmol) as a light
yellow solid; mp 233e235 ꢀC (Et2O); Rf (33% EtOAc/hexane) 0.43; IR
(KBr): 3279, 2988,1661, 1612,1561 cmꢁ1. 1H NMR (300 MHz, DMSO-
4.3.6. Dimethyl 5-methyl-4-phenyl-2H-1,3-oxazine-2,2-dicarboxy-
late (5e). Compound 5e was prepared according to the general
procedure from azirine 1e (100 mg, 0.63 mmol) and diazo com-
pound 2a (100 mg, 0.63 mmol) as a light yellow oil (30 mg, 17%). 1H
NMR (300 MHz, CDCl3):
d
1.73 (d, 3H, J¼1.5 Hz, CH3), 3.89 (s, 6H,
d6):
d
1.02 (t, 3H, J¼6.9 Hz, CH3), 3.81 (s, 3H, CH3O), 4.04 (q, 2H,
3CH3O), 6.87 (q,1H, J¼1.5 Hz, H-6), 7.42e7.51 (m, 5H, ArH). 13C NMR
J¼6.9 Hz, CH2), 7.00 (d, 2H, J¼8.7 Hz, ArH), 7.29 (s, 5H, ArH), 7.52 (d,
(75 MHz, CDCl3):
d 14.1 (CH3), 53.6 (2C, CH3O), 90.0 (C-2), 111.0
2H, J¼8.7 Hz, ArH), 11.93 (s, 1H, NH), 12.23 (s, 1H, CO2H). 13C NMR
(C-5), 128.0, 128.2, 129.8, 136.6 (Ar), 148.0 (C-6), 166.6 (2C, C]O),
(75 MHz, DMSO-d6): d 14.7 (CH3), 56.1 (CH3O), 60.4 (CH2),114.1,115.8

K.V. Zavyalov et al. / Tetrahedron 69 (2013) 4546e4551
4551
Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem. Soc. 1996, 118,
10774e10780; (e) Davies, H. M. L.; Huby, N. J. S. Tetrahedron Lett. 1992, 33,
6935e6938.
3. (a) Alonso, M. E.; Garcia, M. C. J. Org. Chem. 1985, 50, 988e992; (b) Gillespie, R.
J.; Porter, A. E. A. J. Chem. Soc., Perkin Trans. 1 1979, 2624e2628; (c) Maryanoff,
B. E. J. Org. Chem. 1979, 44, 4410e4419; (d) Maryanoff, B. E. J. Org. Chem. 1982,
47, 3000e3002.
4. Manning, J. R.; Davies, H. M. L. J. Am. Chem. Soc. 2008, 130, 8602e8603.
5. Yoshimoto, M.; Ishihara, S.; Nakayama, E.; Soma, N. Tetrahedron Lett. 1972, 13,
2923e2926.
(C-4),119.8 (C-3), 124.2, 127.3, 127.7, 130.9, 131.5,132.9 (Ar), 135.7 (C-
2),138.7,160.2 (Ar),161.0,166.9 (HOC]O, EtOC]O). HRMS (ESI-TOF,
[MþH]þ): calcd for C21H20NO5, 366.1336; found 366.1343. Crystal
data: C21H19NO5, M¼365.37, triclinic, a¼6.9306(3), b¼11.6562(8),
c¼12.6699(10) A,
a
¼102.477(6),
b
¼91.596(5),
g
¼106.323(5)ꢀ,
ꢀ
3
ꢀ
V¼954.79(11) A , T¼120 K, space group P-1, Z¼2,
m
(MoK
a
)¼
0.091 mmꢁ1,11,472 reflections measured, 5312 unique (Rint¼0.0292)
were used in all calculations. The final R1 was 0.0447 (4168>2
s(I))
6. (a) Kametani, T.; Kawamura, K.; Tsubuki, M.; Honda, T. J. Chem. Soc., Chem.
Commun. 1985, 1324e1325; (b) Nozaki, H.; Takaya, H.; Moriuti, S.; Noyori, R.
Tetrahedron 1968, 24, 3655e3669; (c) Tamura, Y.; Takebe, Y.; Mukai, C.; Ikeda,
M. J. Chem. Soc., Perkin Trans. 1 1981, 2978e2981; (d) Crow, W. D.; Gosney, I.;
Ormiston, R. A. J. Chem. Soc., Chem. Commun. 1983, 643e644; (e) Doyle, M. P.;
Griffin, J. H.; Chinn, M. S.; van Leusen, D. J. Org. Chem. 1984, 49, 1917e1925; (f)
Manning, J. R.; Davies, H. M. L. Tetrahedron 2008, 64, 6901e6908.
7. (a) Vedejs, E.; Hagen, J. P. J. Am. Chem. Soc. 1975, 97, 6878e6879; (b) Vedejs, E.;
Hagen, J. P.; Roach, B. L.; Spear, K. L. J. Org. Chem. 1978, 43, 1185e1190; (c)
Nickon, A.; Rodriguez, A. D.; Ganguly, R.; Shirhatti, V. J. Org. Chem. 1985, 50,
and wR2 was 0.1094 (all data).
4.3.11. Ethyl 2-(dimethoxymethyl)-6-methyl-3-phenyl-2H-1,4-
oxazine-5-carboxylate (17). Compound 17 was prepared according
to the general procedure from azirine 1h (220 mg, 1.15 mmol) and
diazo compound 2b (450 mg, 2.9 mmol) as a light yellow oil
(104 mg, 28%). 1H NMR (300 MHz, CDCl3):
d
1.41 (t, 3H, J¼6.9 Hz,
CH3), 2.42 (s, 3H, CH3), 3.26 (s, 3H, CH3O), 3.49 (s, 3H, CH3O),
4.32e4.40 (m, 2H, CH2), 4.55 (d, 1H, J¼7.6 Hz, CH), 5.32 (d, 1H,
J¼7.6 Hz, CH), 7.40e7.42 (m, 3H, ArH), 7.99e8.02 (m, 2H, ArH). 13C
ꢁ
2767e2777; (d) Cere, V.; Paolucci, C.; Pollicino, S.; Sandri, E.; Fava, A. J. Org.
Chem. 1981, 46, 486e490.
8. (a) Kametani, T.; Kanaya, N.; Mochizuki, T.; Honda, T. Tetrahedron Lett. 1983, 24,
221e224; (b) Meth-Cohn, O.; Vuorinen, E. J. Chem. Soc., Chem. Commun. 1988,
138e140; (c) Yamagata, K.; Ohkubo, K.; Yamazaki, M. Liebigs Ann. Chem. 1995,
187e190; (d) Kametani, T.; Kanaya, N.; Mochizuki, T.; Honda, T. Tetrahedron Lett.
1983, 24, 1511e1512; (e) Kametani, T.; Kanaya, N.; Nakayama, A.; Yokohama, S.;
Honda, T. J. Org. Chem. 1986, 51, 1120e1123.
9. (a) Palacios, F.; Ochoa de Retana, A. M.; Marigorta, E. M.; de los Santos, J. M.
In Recent Developments in Heterocyclic Chemistry; Pinho e Melo, T. M. V. D.,
Rocha-Gonsalves, A. M. A., Eds.; Research Signpost: Trivandrum, India, 2007;
pp 27e58; (b) Alves, M. J.; Teixeira Costa, F. In Heterocyclic Targets in
Advanced Organic Synthesis; do CarmoCarreiras, M., Marco-Contelles, J., Eds.;
Research Signpost: Trivandrum, India, 2011; pp 145e172; (c) Pinho e Melo,
T. M. V. D.; d’A Rocha Gonsalves, A. M. Curr. Org. Synth. 2004, 1, 275e292;
(d) Padwa, A. Adv. Heterocycl. Chem. 2010, 99, 1e31; (e) Padwa, A. In
Comprehensive Heterocyclic Chemistry III; Elsevier: Oxford, UK, 2008; Vol. 1,
pp 82e95.
NMR (75 MHz, CDCl3):
d 14.4 (CH3), 17.9 (CH3), 53.2, 56.6 (CH3O),
60.6 (CH2), 69.8 (C-6), 99.2 (CH), 120.1 (C-3), 127.4, 128.2, 130.2,
135.6 (Ar), 148.3 (C-2), 155.1 (C-5), 165.5 (C]O). HRMS (ESI-TOF,
[MþH]þ): calcd for C17H22NO5, 320.1492; found 320.1476.
Acknowledgements
We gratefully acknowledge the financial support of the Russian
Foundation for Basic Research (grant No. 11-03-00186) and Saint
Petersburg State University (grant No. 12.38.78.2012). This research
used resources of the Resource center "Computer center of Saint
Petersburg State University".
10. (a) Khlebnikov, A. F.; Novikov, M. S.; Amer, A. A. Tetrahedron Lett. 2004, 45,
6003e6006; (b) Khlebnikov, A. F.; Novikov, M. S.; Amer, A. A.; Kostikov, R. R.;
Magull, J.; Vidovic, D. Russ. J. Org. Chem. 2006, 42, 515e526.
Supplementary data
11. Khlebnikov, V. A.; Novikov, M. S.; Khlebnikov, A. F.; Rostovskii, N. V. Tetrahedron
Lett. 2009, 50, 6509e6511.
12. Zhao, Y.; Truhlar, D. G. J. Phys. Chem. A 2004, 108, 6908e6918.
13. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112e122.
14. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. J.
1H, 13C NMR spectra of all new compounds and Cartesian co-
ordinates of optimized structures can be found online. Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2013.04.022. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
Appl. Crystallogr. 2009, 42, 339e341.
15. Brahma, S.; Ray, J. K. J. Heterocycl. Chem. 2008, 45, 311e317.
16. Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. J. Am. Chem. Soc. 2003, 125,
4478e4486.
17. Davies, J. R.; Kane, P. D.; Moody, C. J. Tetrahedron 2004, 60, 3967e3977.
18. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman,
J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.;
Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
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